Excel Diet for Homocystinuria: How Can We Use?Binnur TÜZÜN, MD

(1)

Excel Diet for Homocystinuria: How Can We Use?

Binnur TÜZÜN, MD

Address: Özel Çapa Hastanesi, Necip Asım sokak, 23 Çapa-Istanbul-Turkey E-mail: dena_mik@yahoo.com

Corresponding Author: Binnur Tüzün, MD, Özel Çapa Hastanesi, Necip Asım sokak, 23 Çapa-Istanbul-Turkey

Review

Published:

J Turk Acad Dermatol 2010; 4 (1): 04102r

This article is available from: http://www.jotad.org/2009/4/jotad04102r.pdf Key Words: methionine, cysteine, homocystein, diet

Abstract

Background: Methionine restricted diet prevents homocystinuria complications, seems like Marfan syndrome. Homocystinuria is a metabolism disease but Marfan syndrome is a genetic disorder have similar symptoms. But only homocystinuria have neuropsycologic abnormalities and high methionine levels. Homocystein is an intermediate oxidized product, transform both of methionine or cystein. High methionine levels lead to neuropsycologic features, may be also premature ageing, in marfanoid persons with homocystinuria, because of creates over-methylating status in whole organism and also DNA. These high methylating status have found in cancer patients.

Introduction

Diet plays an important role on the body mo- lecular composition. Gout, diabetes, hyper- tension, coeliac and phenylketonuria are known as the diseases that needs a strongly and traditional diet control. Purine control;

sugar control; salt control; gluten-free diet and phenylalanin free diet are recommended for above diseases, respectively.

The clues from the patients have these disea- ses, leads to dermatologists to search the pathways of skin diseases and modern app- roaches to excel diet modifying, from DNA nucleotide sequence and aminoacids to pro- tein synthesis, enzyme and catalysts belongs dermatologic diseases. For example DNA nucleotide methylation differs DNA melting point and autofloures cence of extracted DNA from cancer patients [ 1 ]. The clues from ho-

mocystinuria support cancer, diabetes, ag ing research as a methylating status [2 ].

Marfan Syndrome and Marfanoid Persons with Homocystinuria

Marfan syndrome is an autosomal dominant, elastic fibril disease have an unique phenoty- ping feature. Marfanoid patients have a do- likocephale and thin body structure and accompying defects pectus excavatus or pec- tus carinatus, scolyosis, arachnodactyly [ 3 ], joint hypermobility, muscle contractions [ 4, 5 ], aorta and hearth diseases, ocular finding as lens subluxation [ 5, 6 ], intracranial hypertension, respiratory function disorders because of fibrillin-1 genetic defect [ 7, 8, 9, 10, 11 ]. Homozygotic persons have several features of the syndrome, besides heterozy- gotic persons have only few features [ 12 ].

The most of the marfanoid persons shows homocystinuria or homocystinuria with

Page 1 of 4

(page number not for citation purposes)

(2)

methylmalonic aciduria and needs excell diet modifications [ 7, 9, 13, 14 ] .

Biochemistry of Homocystein Metabolism Blood homocystein and methionine levels are increased and cystein level is decreased in homocystinuria generally. Homocystin, composed of two homocystein molecule by the way of reduction, is an oxydized inter- mediate product. The source of homocystein is generally methionine. Homocystein trans- forms to cystein or methionine by the two- way. Whether homocystein and serin are composed of cystein, or partly is also shows remetylation of homocystein to methionine by the catalyse of B

₁₂

(cyanocobalamin) and folate in healthy persons [ 15, 16, 17 ]. But the patients with homocystinuria blood ho- mocysteine levels are found high as a inter- mediate oxydizing status.

Harmful effects of homocystein appears in the result of the production of oxydants and accumulation of disulphydes in the blood.

The production of oxydants occurs while re- duction of homocystein to homocystin and the accumulation of disulphydes while the reaction of homocystein with protein thiol groups. The most reactive product is thiolac- ton along this pathway [ 15 ].

Cystationin-beta synthase deficiency or ca- talyse deficiency by B6 (pyridoxin) shows ho- mocysteinemia and methioninemia, and mental retardation and seizures appears in homocystinuria Type 1. Eye damage also oc- curs in the result of deficiency in glutathion synthesis as a antioxydant agent, because of low cystein levels [ 18 ].

Homocysteinemia but low methionin levels occurs in type 2, 3, 4 homocystinuria and these patiens do not have mental retardation nor seizures [ 19, 20 ].

Type1 homocystinuria is a rare disease and treated with vitamin B6 and cystein [ 18 ].

Other types of homocystinuria seems more frequently, and improve with vitamin B12 and folate or sometimes diet with methionin because of methionin synthetase deficiency [ 19 ]. Another treatment choice is betain= tri-

methylgliserid (Cystadone 4g/180 ml]) also a methylating agent [ 20, 21, 22 ] .

Enzyme Defects

Until today, some enzyme defects are defined on homocystinuria patients.

1. Methylene tetrahydrofolate reductase defi- ciency (type 2):

Methionin level is decrea- sed in this autosomal recessive enzyme defect. And low cholin levels are defined in brain tissue. Methionin level is increa- sed by giving betain [remethylizating agent] in diet or as a drug. Other enzyme defects lead to low methionin levels are methionin synthase and methionin synthase reductase deficiency [19, 23, 24, 25, 26 ].

2. Cystathionin beta synthase deficiency (type 1):

Homocysteinemia and methioninemia are defined in this autosomal recessive di- sorder with the symptoms malar rash, thin hair and cutis marmorata [ 21, 24, 25, 26, 27, 28 ].

3. Transcobalamin deficiency:

In this auto- somal recessive disorder, vitamin B12 can not transport in the cell, with the symptoms microcephaly, megaloblastic anemia, mental retardation, seizures, ce- rebral atrophy, muscular dystonia (cbIE type), and other type (cbIC) is also autoso- mal recessive disorder with homocystinu- ria and methylmalonic asiduria [1, 6, 29, 30, 31, 32 ].

4. Adenosyl methionin transferase defici- ency: S-adenosylmethionine (AdoMet) lies at an intersection of nucleotide and amino acid metabolism and performs a multitude of metabolic functions. The bioenergetic systems convert environmental calories into ATP, acetyl-Coenzyme A (acetyl-CoA), s-adenosyl-methionine (SAM) and reduced NAD(+) Folate-deficient, iron-rich diet, transgenic mice lacking in apolipoprotein E (ApoE-/- mice) demonstrate impaired activity of glutathione S-transferase (GST), resulting in increased oxidative species within brain tissue despite abnormally high levels of glutathione. These mice also exhibit reduced levels of S-adenosyl met- hionine ([SAM) and increased levels of its hydrolysis product S-adenosyl homocys- teine, which inhibits SAM usage. The mec- hanism by which Vitamin B12 prevents

(page number not for citation purposes) J Turk Acad Dermatol 2010; 4 (1): 04102r. http://www.jotad.org/2010/1/jtad04102r.pdf

Page 2 of 4

(3)

demyelination of nerve tissue is still not known. The evidence indicates that the critical site of B12 function in nerve tissue is in the enzyme, methionine synthase, in a system which requires S-adenosylmet- hionine. In recent years it has been recog- nized that S-adenosylmethionine gives rise to the deoxyadenosyl radical which cataly- zes many reactions including the rearran- gement of lysine to beta-lysine [ 33 ].

Other diseases with homocystinuria Homocystinuria was found in several disease and syndrome as Behçet's disease, diabetes, metabolic syndrome, cardiovascular disea- ses, thrombosis [ 34, 35, 36, 37, 38 ] mental illnes, nephropathia but still in discussion.

Although, marfanoid persons have exactly re- lated homocystinuria and the treatment of homocystinuria is also changed phenotype [ 2, 39 ]. Because of these reasons, homocys- tinuriatest is involved in newborn screening panel, recently [ 40, 41, 42, 43 ].

Excel Diet for Homocystinuria

Methionine restricted diet is need to avoid these foods, contain methionine: meat, fish, yogurt, beans, eggs, onion, garlic, lentils, se- same seeds, wheatgerm, soy protein concen- trate, oat, peanuts, corn yellow, rice brown.

Methionine resticted diet have supported longer life span in experimental animal stu- dies.

Patients can consume these foods contain cysteine: poultry, wheat, broccoli, red pepper [ 44 ].

Onion, garlic, eggs are also contain both of cysteine and methionine.

Cystathionin is composed of methionine and serin by cystathionin beta synthase [ 27 ] and transform to cysteine by cystathionin gamma lysase. Cysteine is nonessential aminoacid but may be essential in newborn, olders, ma- labsorption and metabolic syndromes [ 15 ].

The respectable antioxydant gluthation is composed of cysteine, glycine and glutamic

acid and prevents lens dislocation in this syndrome [ 5, 15 ].

References

1. Cook S, Hess OM. Homocysteine and B vitamins.

Handb Exp Pharmacol 2005; (170): 325-382. PMID:

16596805.

2. Aguirre Errasti C, Egurbide Arberas MV, Martínez Berriotxoa A. Present role of homocysteine in clinical medicine. Med Clin (Barc) 2009; 133: 472-478.

PMID: 19359001

3. Wang XS, Zhang JG, Qiu GX, et al. Clinical diagnosis and surgical treatment of congenital contractural arachnodactyly: analysis of 6 cases. Zhonghua Yi Xue Za Zhi 2008; 88: 615-618. PMID: 18646717 4. Maillot F, Kraus JP, Lee PJ. Environmental influen-

ces on familial discordance of phenotype in people with homocystinuria: a case report. J Med Case Re- ports. 2008; 2: 113. PMID: 18423051

5. Kanigowska K, Grałek M. Lens dislocation in child- ren. Klin Oczna 2006; 108: 90-92. PMID: 16883950 6. Gerth C, Morel CF, Feigenbaum A, Levin AV. Ocular

phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS 2008; 12: 591-596. PMID: 18848477

7. Varlibas F, Cobanoglu O, Ergin B, Tireli H. Different phenotypy in three siblings with homocystinuria.

Neurologist 2009; 15: 144-146. PMID: 19430269 8. Hubmacher D, Cirulis JT, Miao M, et al. Functional

consequences of homocysteinylation of the elastic fiber proteins fibrillin-1 and tropoelastin. J Biol Chem 2009 Nov 4 [Epub ahead of print] PMID: 19889633 9. Heil SG, Hogeveen M, Kluijtmans LA et al. Marfanoid

features in a child with combined methylmalonic aciduria and homocystinuria (CblC type). J Inherit Metab Dis 2007; 30: 811. PMID: 17768669 10. Whiteman P, Hutchinson S, Handford PA. Fibrillin-1

misfolding and disease. Antioxid Redox Signal 2006;

8: 338-346. PMID: 16677079

11.Hubmacher D, Tiedemann K, Bartels R, et al. Modifi- cation of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria. J Biol Chem 2005; 280:

34946-34955. PMID: 16096271.

12. Elsaid MF, Bener A, Lindner M, et al. Are heterocy- gotes for classical homocystinuria at risk of vitamin B12 and folic acid deficiency? Mol Genet Metab 2007;

92: 100-103. PMID: 17686644

13. Gherasim C, Rosenblatt DS, Banerjee R. Polymorphic background of methionine synthase reductase mo- dulates the phenotype of a disease-causing mutation.

Hum Mutat 2007; 28: 1028-1033. PMID: 17554763.

14. Sinclair AJ, Barling L, Nightingale S. Recurrent dystonia in homocystinuria: a metabolic pathogene- sis. Mov Disord 2006; 21: 1780-1782. PMID:

16856143

15. Elshorbagy AK, Nurk E, Gjesdal CG, et al. Homocys- teine, cysteine, and body composition in the Horda- land Homocysteine Study: does cysteine link amino J Turk Acad Dermatol 2010; 4 (1): 04102r. http://www.jotad.org/2010/1/jtad04102r.pdf

Page 3 of 4

(4)

acid and lipid metabolism? Am J Clin Nutr 2008; 88:

738-746. PMID: 18779291

16. Hashimoto T, Shinohara Y, Hasegawa H. Homocys- teine metabolism. Yakugaku Zasshi. 2007; 127:

1579-1592. PMID: 17917419

17. Alberto JM, Hamelet J, Noll C, et al. Mice deficient in cystathionine beta synthase display altered homocysteine remethylation pathway. Mol Genet Metab 2007;

91: 396-398. PMID: 17562377

18. Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 2006; 29:

317-326. PMID: 16763894

19. McCully KS.Homocysteine, vitamins, and vascular disease preven on. Am J Clin Nutr 2007; 86: 1563S- 1568S. PMID: 17991676

20. Ucar SK, Koroğlu OA, Berk O, et al. Titration of betaine therapy to optimize therapy in an infant with 5,10-methylenetetrahydrofolate reductase deficiency.

Eur J Pediatr 2009 May 12 [Epub ahead of print].

PMID: 19434424

21. Yokoi K, Ito T, Ohkubo Y, et al. Long follow up of betaine therapy in two Japanese siblings with cystathionine beta-synthase deficiency. Pediatr Int 2008;

50: 694-695. PMID: 19261122.

22. Lawson-Yuen A, Levy HL The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab 2006; 88: 201-207. PMID: 16545978

23. Birnbaum T, Blom HJ, Prokisch H, et al. Methylene- tetrahydrofolate reductase deficiency (homocystinuria type II) as a rare cause of rapidly progressive tetraspasticity and psychosis in a previously healthy adult. J Neurol 2008; 255: 1845-1846. PMID:

18854913

24. Jakubowski H, Boers GH, Strauss KA. Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. FASEB J 2008; 22: 4071- 4076. PMID: 18708589

25. Bishop L, Kanoff R, Charnas L, et al. Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria. J Child Neurol 2008; 23: 823-828. PMID: 18658082 26. Cohen Aubart F, Sedel F, Papo T. Cystathionine be-

tasynthase and MTHFR deficiencies in adults] Rev Neurol (Paris) 2007; 163: 904-910. PMID: 18033026 27. Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab 2009 Sep 27 [Epub ahead of print] PMID: 19819175 28. Rao TN, Radhakrishna K, Mohana Rao TS, Gurupra- sad P, Ahmed K. Homocystinuria due to cystathionine beta synthase deficiency. Indian J Dermatol Venereol Leprol 2008; 74: 375-378. PMID: 18797062 29. Richard E, Jorge-Finnigan A, Garcia-Villoria J, et al.

Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 2009; 30: 1558-1566. PMID: 19760748 30. Froese DS, Zhang J, Healy S, Gravel RA. Mechanism

of vitamin B12-responsiveness in cblC methylmalo-

nic aciduria with homocystinuria. Mol Genet Metab 2009; 98: 338-343. PMID: 19700356

31. Coelho D, Suormala T, Stucki M, et al. Gene identi- fication for the cblD defect of vitamin B12 metabolism. N Eng J Med 2008;358: 1454-1464. PMID:

18385497

32. Ueland PM, Schneede J. Measurement of methylmalonic acid, homocysteine and methionine in cobalamin and folate deficiencies and homocysteinuria.

Tidsskr Nor Laegeforen 2008; 128: 690-693. PMID:

18337849

33. Couce ML, Bóveda MD, Castiñeiras DE, et al. Hyper- methioninaemia due to methionine adenosyltransfe- rase I/III (MAT I/III) deficiency: Diagnosis in an expanded neonatal screening programme. J Inherit Metab Dis 2008 May 20. PMID: 18560573

34. Tessonnier L, Guedj E, Cano A, et al. Multiple distal pulmonary arterial thromboses revealed by lung scin- tigraphy in a patient with homocystinuria and nor- mal multidetector CT pulmonary angiography. Clin Nucl Med 2009; 34: 42-43. PMID: 19092386 35. Lonn E. Homocysteine in the prevention of ischemic

heart disease, stroke and venous thromboembolism:

therapeutic target or just another distraction? Curr Opin Hematol 2007; 14: 481-487. PMID: 17934354 36. Bendini MG, Lanza GA, Mazza A, et al. Risk factors

for cardiovascular diseases: what is the role for homocysteine? G Ital Cardiol (Rome) 2007; 8: 148-160.

PMID: 17461357

37. Quéré I, Gris JC, Dauzat M. Homocysteine and venous thrombosis. Semin Vasc Med 2005; 5: 183-189.

PMID: 16047270.

38.Moat SJ, McDowell IF. Homocysteine and endothelial function in human studies. Semin Vasc Med 2005;

5: 172-182. PMID: 16047269

39. Azzabi S, Barhoumi A, Omar S, et al. Late revelation of homocysteinuria: clinical, biological and progressive aspects. Pathol Biol (Paris) 2009; 57: 451-455.

PMID: 19046831

40. Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, et al. Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 2009 Nov 13. PMID:

19914636

41. Weisfeld-Adams JD, Morrissey MA, Kirmse BM, et al.

Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a se- condary screening analyte. Mol Genet Metab 2009 Sep 27. [Epub ahead of print] PMID: 19836982 42. Alfonso I, Charria G. Updating neonatal neurometa-

bolic screening. Medicina (B Aires) 2009; 69: 36-40.

PMID: 19359001

43. Kaye CI, Accurso F, La Franchi S, et al. Newborn screening fact sheets. Pediatrics. 2006; 118: e934- e936. PMID: 16950473

44. Lee PJ, Briddon A. A rationale for cystine supplemen- tation in severe homocystinuria. J Inherit Metab Dis 2007; 30: 35-38. PMID: 17186416

J Turk Acad Dermatol 2010; 4 (1): 04102r. http://www.jotad.org/2010/1/jtad04102r.pdf

Page 4 of 4